WO2007148786A1

WO2007148786A1 - Stabilized solid preparation

Info

Publication number: WO2007148786A1
Application number: PCT/JP2007/062592
Authority: WO
Inventors: Shinji Ohmori; Midori Matsuoka
Original assignee: Takeda Pharmaceutical Company Limited
Priority date: 2006-06-23
Filing date: 2007-06-22
Publication date: 2007-12-27
Also published as: EP2042164A4; EP2042164A1; US20100047349A1

Abstract

A stabilized solid preparation having stabilized drug content and stabilized appearance, comprising a main ingredient layer and a coating layer formed on the main ingredient layer, wherein the main ingredient layer comprises a granule or a fine particle comprising a substance capable of being unstabilized when losing water of crystallization and a water-soluble polymer and the coating layer comprises a water-soluble polymer and a sugar.

Description

Specification

Stabilized solid formulation

Technical field

[0001] The present invention relates to stabilization of the content and appearance of a solid preparation containing a drug that becomes unstable when water of crystallization is lost.

Background

[0002] Drug destabilization mechanisms vary. One of these is known to be drugs that become unstable when the crystal water in the drugs is lost. However, a general method has not yet been established for stabilization, and the present situation is that a stabilization method suitable for the drug is being sought. For example, sodium azulene sulfonate is known to exist as a hemihydrate or monohydrate, and it is known that it loses water of crystallization due to heat or the like and becomes unstable ( Non-patent document 1). For stabilization, for example, a method of spray drying together with a polymer compound or a method of freeze-drying (Patent Documents 1 and 2), or a stabilization method by treating with a twin-screw etastrauder (Non-Patent Documents) 1) etc. are presented. However, these methods produce a solid preparation of a drug that becomes unstable when the crystal water is lost due to the need for special equipment to manufacture the solid preparation or the method being complicated. However, it has been difficult to use these methods for industrialization. Therefore, a normal solid preparation production method (for example, using a fluid bed granulator, produce granules for tableting and compress them to obtain uncoated tablets. The uncoated tablets are coated to form coated tablets, etc.) Stabilization within this category was desired.

In addition, in order to increase the therapeutic effect, when manufacturing a combination drug containing other drugs in a drug that is destabilized when crystallization water is lost, a method of spray drying or freeze drying together with the above polymer compound, If a method using a biaxial etastroder is used, other drugs may be decomposed and discolored, making it impossible to produce a stable formulation. Among vitamins, vitamin C is a low-melting compound that easily undergoes a color change due to heat in the presence of moisture, metals, etc., so it melts and softens due to heat and changes appearance. Easy to wake up. Therefore, vitamins, especially vitamins C, vitamin E, to drugs that become unstable when crystallization water is lost In the case of blending a kind, even if the stabilization of the drug content, which is destabilized when crystallization water is lost, the appearance changes, and the appearance may become unstable.

Patent Document 1: Japanese Patent Laid-Open No. 1 50225

Patent Document 2: JP-A-1 50226

^ Patent 1: Nakamichi et al., Stabilization of sodium guaiazulene sulfonate in tablet for prepared preparation using a twin-screw extruder, Eur. J. Pharm. Biopharm., 56, 347-354 (2003)

Disclosure of the invention

Problems to be solved by the invention

[0003] An object of the present invention is to use a water-soluble polymer and further a saccharide to obtain a solid preparation having a stabilized appearance as well as a content of a drug that is destabilized when water of crystallization is lost. Use one or more of fluidized bed granulator, rolling fluidized bed granulator, centrifugal fluidized granulator, extrusion granulator, and agitation granulator, which are production methods used for solid preparations. It is to be provided by the method.

Means for solving the problem

[0004] As a result of diligent studies to achieve the above-mentioned object, the present inventors have used a water-soluble polymer, and further a carbohydrate, in a solid preparation containing a drug that becomes unstable when crystallization water is lost. As a result, it was found that a solid preparation having a stabilized appearance as well as a drug content can be produced.

In the present invention, any of a fluidized bed granulator, a rolling fluidized bed granulator, a centrifugal fluidized granulator, an extrusion granulator, and an agitation granulator, which are production methods used for ordinary solid preparations. One, or possibly two or more devices, are used to prepare fine granules or granules containing the active ingredient (hereinafter referred to as “granules”), and the granules or the granules are compressed into tablets. Thus, it is possible to provide a solid preparation such as a granule obtained by coating the uncoated tablet obtained by coating, a tablet, or a capsule filled with these.

That is, the present invention

(1) Contains an active ingredient layer containing granules or fine particles containing a drug that is destabilized when water of crystallization is lost and a water-soluble polymer, and a water-soluble polymer and carbohydrate formed on the active ingredient layer A stabilized solid formulation having a coating layer to be applied;

(2) The solid preparation according to the above (1), further comprising an intermediate coating layer containing a water-soluble polymer between the active ingredient layer and the coating layer;

(3) The solid preparation according to (1) or (2) above, wherein the granules or fine granules further contain a saccharide;

(4) Solubility power in water at 20 ° C of a drug that is destabilized when water of crystallization is lost 0. lw / w% or more of the solids according to (1) to (3) above, Formulation;

(5) The solid preparation according to the above (4), wherein the drug that is destabilized when water of crystallization is lost is sodium azulene sulfonate; a group consisting of sesame, povidone, copolyvidone, polyvinylinole noleconole, gum arabic, and punoreran Any one of the above-mentioned (1) to (3), which is one or more selected from:

(7) The above (1) to (1), wherein the saccharide is one or more selected from the group consisting of erythritol, maltitol, powdered reduced maltose water mannitol, refined sucrose, sucrose, trehalose, sorbitol, xylitol and lactose. 3) any force, the solid preparation according to 1,

(8) The content of the drug that is destabilized when the crystal water is lost is 10% by weight or less of the total amount of the preparation, any one of the above (1) to (3), the solid preparation according to 1,

(9) The above-mentioned (1) to (3) containing 1 to 100 parts by weight of a water-soluble polymer for 1 part by weight of a drug that becomes unstable when water of crystallization is lost. Solid formulations;

(10) The solid preparation according to (1) or (3) above, which contains 1 to 1000 parts by weight of a saccharide for 1 part by weight of a drug that becomes unstable when water of crystallization is lost ;

(11) A solid preparation according to any one of (1) to (3) above, which is a tablet or granule, or a capsule containing the tablet or granule;

(12) Preparation of granules or fine granules using a solution in which a drug that is destabilized when water of crystallization is lost and a water-soluble polymer are dissolved, and production using the granules or fine grains in A method for producing a solid preparation according to (1) or (2) above,

(13) Prepare granules or fine granules using a solution that dissolves the drug, water-soluble polymer and sugar that are destabilized when water of crystallization is lost. thing A method for producing a solid preparation according to the above (3), characterized in that

The invention's effect

[0005] According to the present invention, a solid preparation having a stabilized appearance as well as a content of a drug that is destabilized when water of crystallization is lost due to a water-soluble polymer and also a saccharide. Use one or more of fluidized bed granulator, rolling fluidized bed granulator, centrifugal fluidized granulator, extrusion granulator, and stirring granulator, which are the production methods used in Provided by the power S.

BEST MODE FOR CARRYING OUT THE INVENTION

[0006] The solid preparation according to the present invention comprises an active ingredient layer containing granules or fine particles containing a drug and a water-soluble polymer that are destabilized when water of crystallization is lost, and a water-soluble substance formed on the active ingredient layer. It is a stabilized solid preparation having a coating layer containing a high molecule and a carbohydrate, and the active ingredient layer of the solid preparation may contain a sugar, and between the active ingredient layer and the covering layer. It may have an intermediate coating layer. Here, in the specification, “being destabilized when water of crystallization is lost” means that the crystal structure is changed, destabilized and decomposed by losing water of crystallization in the drug. Therefore, “stabilized” means that the content of the active ingredient contained in the solid preparation and the appearance are changed by suppressing the separation of the crystal water from the drug that becomes unstable when the crystal water is lost. Suppressed! /, What to do! /

[0007] Examples of the drug that is destabilized when crystallization water is lost in the present invention include sodium azulensulphonate, sodium plasterone sulfate, ampicillin trihydrate, cefixime trihydrate, and the like. From the viewpoint of formulation, a drug that becomes unstable when crystallization water is lost in the present invention has a solubility in water at 20 ° C of 0.1 lw / w% or more, preferably lw / w% or more. Those such as sodium azulene sulfonate are preferred. In the present invention, the content of the drug that becomes unstable when crystallization water is lost in the solid preparation is 10% by weight or less of the total amount of the solid preparation from the viewpoint of the size and amount of the solid preparation to be taken. 5% by weight or less.

[0008] In addition, the active ingredient layer of the present invention may contain other active ingredients in addition to the drug that becomes unstable when water of crystallization is lost. Examples of such active ingredients include, but are not limited to, vitamins, antacids, stomachic medicines, digestives, antipruritics, analgesic antispasmodics, mucosal repair agents, and the like. I'll use the power to join myself.

Examples of the vitamins include ascorbic acid, calcium ascorbate, and sodium ascorbate as vitamin C. Examples of vitamin E include succinic acid dl-α tocopheronorecanoleum, konsuccinic acid d- _α tocopheronole, and acetic acid d-α-tocopheronole S. Also, L-cystine, vitamin B1 (thiamine hydrochloride, thiamine nitrate, fursultiamine hydrochloride, discetiamine hydrochloride, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, benfotiamine), vitamin Β2 (riboflavin, riboflavin phosphate) , Riboflavin butyrate), vitamins Β6 (pyridoxine hydrochloride, pyridoxal phosphate), vitamin B12 (cyancobalamin, hydroxocobalamin acetate, mecobalamin), calcium pantothenate

, Calcium pantothenate type S, nicotinic acid, nicotinic acid amide, gamma mono oryzanol, orotic acid, gnolecronolataton, glucuronic acid amide, goyonin, hesperidin, biotin, chondroitin sulfate sodium and the like.

Antacids include dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide magnesium, aluminum hydroxide gel, aluminum hydroxide and sodium bicarbonate. Precipitation product, aluminum hydroxide 'magnesium carbonate mixed dry gel, aluminum hydroxide' magnesium carbonate 'calcium carbonate coprecipitation product, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, magnesium metasilicate aluminate Anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, amino amino acid, dihydroxyaluminum amino acetate, funnel extract and the like.

As stomachic medicines, aloe, wikiweed, turmeric, ovata, ollen, processing daisyu, koujin, kopoku, shokiyo, assembly, keihi, daiou, chikusennin, chimpi, spruce, nigaki, carrot, nocturnal force, hop, Examples include wikiyo oil, kayhi oil, shokiyo oil, spruce oil, mint oil, lemon oil, 1 menthol, betaine hydrochloride, carnitine chloride, and dry yeast.

Examples of the digestive agent include starch digestive enzyme, protein digestive enzyme, fat digestive enzyme, fibrin-degrading enzyme, ursodeoxycholic acid, bile powder and the like.

Antidiarrheal agents include atalinol, berberine chloride, guaiacol, creosote, Bismuth tyrrate, bismuth subnitrate, bismuth subcarbonate, bismuth subgallate, tannic acid

, Kaolin, pectin, medicinal charcoal, calcium lactate, precipitated calcium carbonate, hydrogen phosphate, and so on.

Examples of the analgesic and antispasmodic agent include papaverine hydrochloride, ethyl aminobenzoate and the like. Examples of the mucosal repairing agent include aldioxa, L-glutamine, copper chlorophyllin potassium, copper chlorophyllin sodium, methylmethionine sulfone chloride, dimethylpolysiloxane and the like.

[0009] The water-soluble polymer that can be used in the present invention is a polymer having a solubility in water at 20 ° C of 1w / w% or more, preferably a polymer having 3w / w% or more, More preferably, a polymer of 5 w / w% or more is preferable. Specifically, as the water-soluble polymer, one or more selected from hydroxy-opened pinolecenolose, hydroxypropinoremethinorescenellose, povidone, copolyvidone, polyvinyl alcohol, gum arabic, and pullulan. Is preferably used.

The compounding amount is 1 to 100 parts by weight, preferably,! To 50 parts by weight with respect to 1 part by weight of the drug which becomes unstable when crystallization water is lost.

[0010] Sugars that can be used in the present invention include erythritol, maltitol, powdered maltose starch syrup, mannitol, purified sucrose, sucrose, trehalose, sorbitol, xylitol, lactose, and reduced maltose starch syrup. , Glucose, maltose, latitol, etc. Among them, erythritol, maltitol, powdered reduced maltose starch, mannitol, purified sucrose, sucrose, trehalose, sonorebitole, xylitoleole, lactose I prefer to use one or more! / ,.

The compounding amount is from 1 to 1000 parts by weight, preferably from! To 500 parts by weight with respect to 1 part by weight of the drug that becomes unstable when water of crystallization is lost.

[0011] Examples of the solid preparation of the present invention include granules (including coated granules), tablets (eg, uncoated tablets, sugar-coated tablets, thin-layer sugar-coated tablets, film-coated tablets, chewable tablets, orally disintegrating tablets) , Laminated tablets, dry-coated tablets, sustained-release tablets), capsules (hard capsules, soft capsules), powder inhalants and the like.

The solid preparation of the present invention is usually prepared using a pharmacologically acceptable carrier or the like that is usually blended. It can be manufactured by the method. In particular, use one or more of fluidized bed granulation method, rolling fluidized bed granulation method, centrifugal fluidized granulation method, extrusion granulation method, and stirring granulation method that are usually used. Can do. That is, a core particle (granule, uncoated tablet, etc.) corresponding to the main drug layer of the solid preparation of the present invention is produced using an active ingredient such as a drug that becomes unstable when water of crystallization is lost and an additive such as a carrier. It is possible to manufacture by coating the core particles with a coating agent. In addition, when the granules or tablets obtained in this way are small-sized, they may be filled into capsules to form capsules.

As a method for producing a core particle, for example, a granule or a fine particle is prepared using a solution in which an active ingredient such as a drug which becomes unstable when water of crystallization is lost, a water-soluble polymer and a carbohydrate are dissolved, and then, Examples thereof include a method in which the obtained granule or fine granule and an additive are mixed and tableted to produce an uncoated tablet. Furthermore, as another manufacturing method, the drug is used as a solution, a water-soluble polymer is added to the solution (and a saccharide may be further added), and the solution is added to saccharides, celluloses, inorganic substances, etc. There is also a method of coating a core particle or a core tablet such as an excipient or a granule, fine particle or uncoated tablet that does not contain the drug.

Examples of the pharmacologically acceptable carrier used in the production of the solid preparation of the present invention include various organic or inorganic carrier substances commonly used as a preparation material. For example, excipients, binders, disintegrants, lubricants. Examples of the agent include a lubricant, a fluidizing agent, and a surfactant. Moreover, additives, such as an antioxidant, a corrigent, a coloring agent, and a fragrance | flavor, can also be used as needed.

Examples of excipients include erythritol, maltitol, powdered reduced maltose starch, mannitol, purified sucrose, sucrose, trehalose, sorbitol, xylitol, lactose, reduced maltose starch, glucose, maltose, ratathitol, corn starch, Examples thereof include crystalline cellulose, powdered cellulose, calcium monohydrogen phosphate, calcium hydrogen phosphate, anhydrous hydrogen phosphate calcium, calcium lactate, and precipitated calcium carbonate.

Examples of the binder include hydroxypropylcellulose, pregelatinized starch, sucrose, ze-noreoxymethinoresenorelose, nabenoximethinoresenorelose sodium, polyvinylinorepyrrolidone, polybutal alcohol, crystalline cellulose, dextrin, Pullulan etc. It is.

Disintegrants include croscarmellose sodium, low-substituted hydroxypropyl cellulose, canolemellose canoleum, corn starch, canolepoxymethinorestarch sodium, hydroxypropyl starch, partially pregelatinized starch, crospovidone, etc. Is mentioned.

Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, macrogol 6000, and the like.

Examples of the fluidizing agent include light caustic anhydride, hydrous silicon dioxide, kaolin and the like.

Examples of surfactants include polysorbate (polysorbate 80, etc.), polyoxyethylene 'polyoxypropylene copolymer, sodium lauryl sulfate, etc. Antioxidants include, for example, sodium ascorbate, L-cysteine, sodium sulfite, etc. Is mentioned.

Examples of the corrigent include citrate, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharin, sodium glycyrrhizin, sodium glutamate, 5, sodium monoinosinate, 5, sodium monoguaurate, etc. Is mentioned.

Examples of colorants include riboflavin, vitamin Β12, titanium oxide, yellow iron sesquioxide, iron sesquioxide, edible red No. 2, edible red No. 3, edible red No. 102, edible red No. 104, edible red No. 105, edible Red No. 106, Edible Yellow No. 4, Edible Yellow No. 5, Edible Green No. 3, Edible Blue No. 1, Edible Blue No. 2, Copper Chlorophyll Sodium, Copper Chlorophyll, etc. And oil, eucalyptus oil, orange oil, thioji oil, turpentine oil, wikiy oil and vanillin.

The coating layer covering the active ingredient layer in the present invention is not particularly limited as long as it is a coating layer containing a carbohydrate. Examples of such saccharides include purified sucrose, sucrose, erythritol, trehalose, maltitol, powdered reduced maltose starch syrup, mannitol, sonorebitole, xylitol, and lactose. Using one or more of these carbohydrates, sugar coating or thin layer By applying sugar coating (for example, see JP-A-2002-179559), the solid preparation of the present invention is stabilized.

As a method for coating the active ingredient layer in the present invention, there is a method in which core particles such as condyles, fine particles, and plain tablets containing the drug are produced in advance, and the core particles are coated. Another method is to coat the drug directly.

The coating layer containing a saccharide used in the present invention is not particularly limited as long as it is a sugar coating using a sugar such as purified sucrose or a thin layer sugar coating using a sugar such as erythritol. If necessary in addition to the saccharide used for coating, an excipient, a binder, a lubricant, a colorant, a fragrance and the like may be added to the coating solution.

Examples of excipients used in the coating liquid include wheat starch, rice starch, corn starch, potato starch, precipitated calcium carbonate, kaolin, hydrous silicon dioxide, calcium silicate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. Binders used in the coating solution include gum arabic powder, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), methylcellulose, hydroxychetinoresenorerose, force noreoxymethylenoreethinorenorose , Povidone (PVP), polyvinyl alcohol (PVA), pullulan, dextrin, pregelatinized starch, hydroxy-pilled starch, tragacanth powder, crystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), and the like.

Examples of the lubricant used in the coating liquid include talc, light anhydrous caustic acid, Macrogol 6000, magnesium stearate, calcium stearate, sucrose fatty acid ester and the like.

Coloring agents used in the coating solution include riboflavin, vitamin B12, titanium oxide, yellow ferric oxide, ferric oxide, edible red No. 2, edible red No. 3, edible red No. 102, edible red No. 104, and edible red 105. No., Edible Red No. 106, Edible Yellow No. 4, Edible Yellow No. 5, Edible Green No. 3, Edible Blue No. 1, Edible Blue No. 2, Copper Chlorophyll Sodium, Copper Chlorofinole and the like.

Perfumes used in the coating liquid include menthol, hearth oil, eucalyptus oil, oren Di oil, Thioji di oil, turpentine oil, Wikiyo oil, vanillin and the like.

In the solid preparation of the present invention, when the coating layer is coated or stored under high humidity, the active ingredient may be mixed into the coating layer. Therefore, in order to prevent this, an intermediate film is formed between the active ingredient layer and the coating layer. A layer may be provided. As long as this purpose is achieved, the material of the intermediate film layer is not limited. For example, it is preferable to use a coating substrate similar to the above coating layer.

[0014] The fluidized bed granulator, rolling fluidized bed granulator, centrifugal fluidized granulator, extrusion granulator, and agitation granulator used in the present invention are not limited. For example, Baurek Company, Freund Industrial Company, and Fuji Baudal Company may be used.

Example

[0015] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1

Purified 1800 g calcium ascorbate, 150 g d-α-tocopherol succinate, 354 g crystal cell mouth (Ceras KG802), 36 g calcium silicate (florite RE), 12 g sodium azulenesulfonate, 144 g HPC-L, 240 g erythritol The aqueous solution dissolved in 2256 g of water was sprayed with a fluid bed granulator (MP-10, Norrec) for granulation. The obtained granulated powder was sized using a sizing machine (Power Mill, Showa Mechanics) to obtain a sized powder. Blender (Tumbler blender) 2371.2g of sized powder, 624g of L-cysteine, 145.6g of crystalline cellulose (Ceras KG802), 156g of low substituted hydroxypropyl cellulose (L-HPC, LH31), 31.2g of magnesium stearate 15L) and Showa Chemical Machinery) to obtain a mixed powder. Using a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho), the resulting mixed powder was put into a plain tablet with a weight of 320 mg and a thickness of 5.54 mm using a pestle with a 8.8 mm diameter mortar and a curvature radius of 7 mm. Obtained.

300 g of the resulting uncoated tablet is charged into a coating machine (Neuko Coater MIM, Freund Sangyo), 90 g of hydroxypropylmethylcellulose (TC-5MW) and 10 g of talc are dissolved in 900 g of purified water and the suspended coating solution is sprayed onto the uncoated tablet Then, 6 mg per tablet was coated to obtain undercoated (UC) tablets. Next, UC Tablets, erythritol 530g, talc 280g, titanium oxide 20g, crystalline cellulose (Avicel PH-F20) 50g, gum arabic powder 120g purified water 150 The coating solution dissolved and suspended in Og was sprayed, and 114 mg per tablet was coated to obtain build-up coating (BC) tablets. Subsequently, a BC tablet was coated with 15 mg of each tablet using a coating solution in which 360 g of erythritol and 40 g of polyethylene glycol 6000 (PEG6000) were dissolved in 600 g of purified water to obtain a syrup-coated (SC) tablet. The SC tablet was poured into a squeezed solution in which carnauba wax, shellac pearl, castor oil, ethanol, and n-hexane were dissolved, and dried to obtain a squeezed sugarless thin-layer sugar-coated tablet.

[0016] Example 2

1800 g calcium ascorbate, 150 g d-α-tocopherol succinate, 354 g crystal cell mouth (Ceras KG802), 36 g calcium silicate (florite RE), 12 g sodium azulenesulfonate, 144 g PVP 90, 240 g erythritol The aqueous solution dissolved in 2256 g was sprayed with a fluid bed granulator (MP-10, Norrec) for granulation. The obtained granulated powder was sized using a sizing machine (Power Mill, Showa Mechanics) to obtain a sized powder. Blender (Tumbler blender) 2371.2g of sized powder, 624g of L-cysteine, 145.6g of crystalline cellulose (Ceras KG802), 156g of low substituted hydroxypropyl cellulose (L-HPC, LH31), 31.2g of magnesium stearate 15L) and Showa Chemical Machinery) to obtain a mixed powder. Using a rotary tableting machine (Correct 12HUK, Kikusui Seisakusho), the resulting mixed powder was put into a plain tablet with a weight of 320 mg and a thickness of 5.54 mm using a pestle with a 8.8 mm diameter mortar and a curvature radius of 7 mm. Obtained.

The obtained uncoated tablets were subjected to sugarless thin-coated sugar coating as in Example 1 to obtain sugarless thin-layered sugar-coated tablets.

[0017] Example 3

1800 g calcium ascorbate, 150 g d-α-tocopherol succinate, 354 g crystal cell mouth (Ceras KG802), 36 g calcium silicate (florite RE), 12 g azulene sulfonate, 144 g HPC-L to 2256 g purified water The dissolved aqueous solution was sprayed with a fluid bed granulator (MP-10, Norrec) and granulated. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Mechanics) to obtain a sized powder. Mixing machine (Tumbler mixer (15L), 2163.2g of sized powder, 624g of L-cystine, 145.6g of crystalline cellulose (Ceras KG802), 156g of low substituted hydroxypropylcellulose (LH PC, LH31) ) And Showa Chemical Machinery) to obtain a mixed powder. The resulting mixed powder is turned into a rotary tableting machine ( Collect 12HUK (Kikusui Seisakusho) was used to obtain an uncoated tablet with a weight of 300 mg and a thickness of 5.26 mm using a pestle with a 8.8 mm diameter mortar and a radius of curvature of 7 mm.

[0018] Example 4

1800 g calcium ascorbate, 150 g succinate d α tocopherol, 354 g crystal cell mouth (Ceras KG802), 36 g calcium silicate (florite RE), 12 g azulene sulfonate and 144 g PVP 90 were dissolved in 2256 g purified water. The aqueous solution was sprayed with a fluidized bed granulator (MP-10, Norrec) for granulation. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Mechanics) to obtain a sized powder. A blender (Tumbler blender (15L), 2163.2g of sized powder, 624g of L-cystine, 145.6g of crystalline cellulose (Ceras KG802), 156g of low-substituted hydroxypropyl cellulose (LH PC, LH31) and 31.2g of magnesium stearate ) And Showa Chemical Machinery) to obtain a mixed powder. The resulting mixed powder is rotary tableting machine (collect 12HUK, Kikusui Seisakusho Co., Ltd.) using a punch with a 8.8mm diameter mortar and a radius of curvature 7mm to obtain an uncoated tablet with a weight of 300mg and a thickness of 5.29mm. It was.

[0019] Comparative Example 1

Aqueous solution of 12g sodium azulenesulfonate, 1800g calcium ascorbate, 150g succinic acid d-a tocopherol 150g, 354g crystalline cellulose (Ceras KG802), 36g calcium silicate (FLORITE RE), 144g HPC-L in 2256g purified water Was sprayed with a fluidized bed granulator (MP-10, Norrec) and granulated. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Mechanics) to obtain a sized powder. Mixing machine (Tumbler mixer (15L), 2163.2g of sized powder, 624g of L-cystine, 145.6g of crystalline cellulose (Ceras KG802), 156g of low substituted hydroxypropylcellulose (LH PC, LH31) ) And Showa Chemical Machinery) to obtain a mixed powder. The resulting mixed powder is rotary tableting machine (collect 12HUK, Kikusui Seisakusho Co., Ltd.), using a pestle with a diameter of 8.8 mm and a radius of curvature of 7 mm to obtain an uncoated tablet with a weight of 300 mg and a thickness of 5.26 mm. It was. [0020] Comparative Example 2

A solution of 12 g of sodium azulene sulfonate, 1800 g of calcium ascorbate, 150 g of succinic acid d-a tocopherol 150 g, 354 g of crystalline cellulose (Ceras KG802), 36 g of calcium silicate (FLORITE RE) in 2256 g of purified water. Sprayed and granulated with a fluid bed granulator (MP-10, Norrec). The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Mechanics) to obtain a sized powder. A blender (Tumbler blender (15L), 2163.2g of sized powder, 624g of L-cystine, 145.6g of crystalline cellulose (Ceras KG802), 156g of low-substituted hydroxypropyl cellulose (LH PC, LH31) and 31.2g of magnesium stearate ) And Showa Chemical Machinery) to obtain a mixed powder. The resulting mixed powder is rotary tableting machine (collect 12HUK, Kikusui Seisakusho Co., Ltd.) using a punch with a 8.8mm diameter mortar and a radius of curvature 7mm to obtain an uncoated tablet with a weight of 300mg and a thickness of 5.29mm. It was.

[0021] Sodium azulenesulfonate content stable

The tablets of Examples;! To 4 and Comparative Examples 1 and 2 were sealed in glass bottles at 60 ° C. for 2 weeks, and the content of sodium azulenesulfonate in the tablets was measured by the HPLC method and evaluated by the residual ratio.

[0022] Sodium azulenesulfonate content test

Take 20 tablets and crush them with a crusher to make the sample powder. Add 50 mL of the lysate to the sample powder (1 tablet), perform shaking extraction for 30 minutes, then centrifuge (approximately 9400 X g, 10 minutes), and add 5 mL of the resulting supernatant to 5 mL of the supernatant. 5 mL of standard solution was added and mixed to prepare a sample solution. The sample solution was measured under the following HPLC conditions. Note that methanol / water (6/4) was used as the solution. As an internal standard solution, bis (2-ethylhexyl) phthalate methanol solution was used. HPLC conditions

Detector: UV absorptiometer (measurement wavelength 285nm)

Column: YMC- Pack AM-3E2 (YMC)

Column temperature: 50 ° C

Mobile phase: 0.003mol / L trioctylamine-containing methanol / water (17/3) mixture (ρΗ6 · 0) Flow rate: 0.35mL / min

[table 1] Sodium content of azulene sulfonate content stability (residual rate (¾), stored at 60 ° C for 2 weeks)

[0023] Appearance stability

The tablets of Examples 1 and 2 and Comparative Examples 1 and 2 were opened at 40 ° C and 75% RH for 1 month, and changes in the appearance of the tablets were measured with a color computer (S & M color computer, Suga Tester). The color difference (ΔΕ) was evaluated. In Examples 1 and 2, after opening the container at 40 ° C and 75% RH for 1 month, the coating layer was scraped with a cutter, and the change in the appearance of the internal tablet was similarly evaluated by the color difference (ΔΕ).

[Table 2]

In Examples 1 and 2, compared to Comparative Examples 1 and 2, not only the drug content but also the external appearance of the tablet and the inside of the tablet were stabilized.

Claims

The scope of the claims

[I] Contains a main drug layer containing granules or fine particles containing a drug and water-soluble polymer that are destabilized when water of crystallization is lost, and a water-soluble polymer and a carbohydrate formed on the main drug layer A stabilized solid preparation having a coating layer.

[2] The solid preparation according to claim 1, further comprising an intermediate coating layer containing a water-soluble polymer between the active ingredient layer and the coating layer.

[3] The solid preparation according to claim 1 or 2, wherein the granules or fine granules further contain a saccharide.

[4] The solid preparation according to claim 1, wherein the drug destabilizing when water of crystallization is lost has a solubility power in water at 20 ° C of not less than 0.1 lw / w%; .

5. The solid preparation according to claim 4, wherein the drug preparation is sodium azulene sulfonate, which is destabilized when water of crystallization is lost. The solid preparation according to any one of claims 1 to 3, wherein the solid preparation is at least one selected from the group consisting of supo, povidone, copolyvidone, polyvinylino leno cornole, gum arabic and punoleran.

[7] The saccharide according to claim 3, wherein the saccharide is one or more selected from the group consisting of erythritol, maltitol, powdered reduced maltose water mannitol, purified sucrose, sucrose, trehalose, sorbitol, xylitol and lactose; ! /, Slippery solid preparation according to item 1.

[8] The solid preparation according to any one of claims 1 to 3, wherein the content of the drug that becomes unstable when water of crystallization is lost is 10% by weight or less of the total amount of the preparation.

[9] The solid preparation according to any one of claims 1 to 3, which comprises:! To 100 parts by weight of a water-soluble polymer with respect to 1 part by weight of the drug that becomes unstable when water of crystallization is lost.

[10] The solid preparation according to any one of claims 1 to 3, comprising 1 to 1000 parts by weight of a saccharide with respect to 1 part by weight of the drug that becomes unstable when water of crystallization is lost.

[I I] The solid preparation according to any one of claims 1 to 3, which is a tablet or granule, or a capsule containing the tablet or granule.

[12] Prepare condylar particles or fine granules using a solution in which water and water-soluble polymers are dissolved, which are destabilized when water of crystallization is lost, and then use the granules or fine grains to produce them. Characterized by The method for producing a solid preparation according to claim 1 or 2.

Prepare a granule or fine granule using a solution that dissolves the drug, water-soluble polymer, and sugar that are destabilized when water of crystallization is lost. The method for producing a solid preparation according to claim 3, characterized by the above.